Despite widespread vaccination initiatives, influenza remains a major cause of mortality and morbidity. Each year between 250 000 and 500 000 deaths are attributed to seasonal influenza with associated annual healthcare costs of $14 billion in the US alone. Vaccination programmes aim to minimise the burden of seasonal influenza, with the majority of vaccines available at the time of writing designed to generate protective antibody-mediated immunity. This serological protection is highly strain specific, especially if generated using killed virus preparations. The success of seasonal vaccination programmes is dependent upon both the reliable predictive modelling of strain circulation and the lack of viral coat protein mutation enabling immune evasion during a flu season.
Furthermore, influenza can extend beyond its usual seasonal impact by shifting its antigenic profile significantly enough to escape from protective immunity on a global scale. If such pandemic strains carry traits of high virulence and pathogenicity then associated mortality can be devastating, as seen in the 1918 outbreak.
Influenza viruses can evade established protective immune responses by two distinct mechanisms: The gradual antigenic drift of viral surface epitopes results from low fidelity viral replication and adoption of mutations which eventually allows escape from established serological immunity. Less common, but with significant impacts on global health, is the emergence of entirely new viral strains arising from the reassortment of influenza virus RNA from different strains in a common host. The emerging novel pathogen can result in a pandemic where the new flu strain can spread rapidly through communities which lack protective immunity to novel viral proteins.
In the context of these events where there are no pre-existing protective antibodies, T cells may mediate protection or limit the severity of influenza associated illness (Kreijtz J H et al., Vaccine 25 612-620 2007). Pre-existing T cell responses have been shown to modulate influenza severity in the context of existing antibodies (McMichael et al., N Engl J Med 309, 13-17, 1983) but the role of protective cell mediated immunity (CMI) in sero-negative individuals naïve to a particular flu strain is not understood.
Lee et al. (J Clin Invest 118, 3478-3490, 2008) showed that memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. However, the experiments were carried out ex vivo and do not necessarily accurately reflect the clinical picture.
Despite of these reports, at the time of writing the main focus of research remains the search for a ‘super-antibody’ that is capable of targeting all known subtypes of the influenza A virus.
In July 2011, Corti et al. (Science 28 Jul. 2011: 1205669) reported on the isolation of a neutralising monoclonal antibody that recognised the hemagglutinin (HA) glycoprotein of all 16 known subtypes of influenza A and neutralised both group 1 and group 2 influenza A viruses using a single-cell culture method for screening large numbers of human plasma cells. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analysed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. Based on these results, it was reported that the antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
Announcing these findings, Dr A. Lanzavecchia, who led the study, also opined that approaches to developing a universal vaccine that did not rely on antibodies were unlikely to work (report in The Independent, 29 Jul. 2011).
Nevertheless, there remains a need in the art for new therapeutic agents, and methods for identifying such agents, for use in the treatment viral infections, including influenza A, especially in patients who do not have pre-existing protective antibodies for the strain of virus that is the cause of the infection.